PMID- 32949572
OWN - NLM
STAT- MEDLINE
DCOM- 20210310
LR  - 20211204
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Linking)
VI  - 334
DP  - 2020 Dec
TI  - Unique signatures of stress-induced senescent human astrocytes.
PG  - 113466
LID - S0014-4886(20)30297-1 [pii]
LID - 10.1016/j.expneurol.2020.113466 [doi]
AB  - Senescence was recently linked to neurodegeneration and astrocytes are one of the 
      major cell types to turn senescent under neurodegenerative conditions. Senescent 
      astrocytes were detected in Parkinson's disease (PD) patients' brains besides 
      reactive astrocytes, yet the difference between senescent and reactive astrocytes 
      is unclear. We aimed to characterize senescent astrocytes in comparison to 
      reactive astrocytes and investigate differences and similarities. In a cell 
      culture model of human fetal astrocytes, we determined a unique senescent 
      transcriptome distinct from reactive astrocytes, which comprises dysregulated 
      pathways. Both, senescent and reactive human astrocytes activated a 
      proinflammatory pattern. Astrocyte senescence was at least partially depending on 
      active mechanistic-target-of-rapamycin (mTOR) and DNA-damage response signaling, 
      both drivers of senescence. To further investigate how PD and senescence connect 
      to each other, we asked if a PD-linked environmental factor induces senescence 
      and if senescence impairs midbrain neurons. We could show that the PD-linked 
      pesticide rotenone causes astrocyte senescence. We further delineate, that the 
      senescent secretome exaggerates rotenone-induced neurodegeneration in midbrain 
      neurons differentiated from human induced pluripotent stem cells (hiPSC) of PD 
      patients with alpha-synuclein gene (SNCA) locus duplication.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Simmnacher, Katrin
AU  - Simmnacher K
AD  - Department of Stem Cell Biology, Friedrich-Alexander-Universitat (FAU) 
      Erlangen-Nurnberg, 91054 Erlangen, Germany.
FAU - Krach, Florian
AU  - Krach F
AD  - Department of Stem Cell Biology, Friedrich-Alexander-Universitat (FAU) 
      Erlangen-Nurnberg, 91054 Erlangen, Germany; Department of Cellular and Molecular 
      Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
FAU - Schneider, Yanni
AU  - Schneider Y
AD  - Department of Molecular Neurology, FAU Erlangen-Nurnberg, 91054 Erlangen, 
      Germany.
FAU - Alecu, Julian E
AU  - Alecu JE
AD  - Department of Stem Cell Biology, Friedrich-Alexander-Universitat (FAU) 
      Erlangen-Nurnberg, 91054 Erlangen, Germany.
FAU - Mautner, Lena
AU  - Mautner L
AD  - Department of Stem Cell Biology, Friedrich-Alexander-Universitat (FAU) 
      Erlangen-Nurnberg, 91054 Erlangen, Germany.
FAU - Klein, Paulina
AU  - Klein P
AD  - Department of Stem Cell Biology, Friedrich-Alexander-Universitat (FAU) 
      Erlangen-Nurnberg, 91054 Erlangen, Germany.
FAU - Roybon, Laurent
AU  - Roybon L
AD  - Stem Cell Laboratory for CNS Disease Modeling, MultiPark and Lund Stem Cell 
      Center, Department of Experimental Medical Science, Faculty of Medicine, Lund 
      University, 22184 Lund, Sweden.
FAU - Prots, Iryna
AU  - Prots I
AD  - Department of Stem Cell Biology, Friedrich-Alexander-Universitat (FAU) 
      Erlangen-Nurnberg, 91054 Erlangen, Germany.
FAU - Xiang, Wei
AU  - Xiang W
AD  - Department of Molecular Neurology, FAU Erlangen-Nurnberg, 91054 Erlangen, 
      Germany.
FAU - Winner, Beate
AU  - Winner B
AD  - Department of Stem Cell Biology, Friedrich-Alexander-Universitat (FAU) 
      Erlangen-Nurnberg, 91054 Erlangen, Germany. Electronic address: 
      beate.winner@fau.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200917
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 03L9OT429T (Rotenone)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Astrocytes/drug effects/*metabolism
MH  - Cell Survival/drug effects/physiology
MH  - Cells, Cultured
MH  - Cellular Senescence/drug effects/*physiology
MH  - Female
MH  - Humans
MH  - Hydrogen Peroxide/toxicity
MH  - Induced Pluripotent Stem Cells/drug effects/*metabolism
MH  - Middle Aged
MH  - Oxidative Stress/drug effects/*physiology
MH  - Parkinson Disease/metabolism/pathology
MH  - Rotenone/toxicity
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - Transcriptome/drug effects/*physiology
OTO - NOTNLM
OT  - Alpha synuclein
OT  - Astrocyte neuron interplay
OT  - Parkinson's disease
OT  - Reactive astrocyte
OT  - Rotenone
OT  - Senescence
OT  - iPSC derived neurons
EDAT- 2020/09/20 06:00
MHDA- 2021/03/11 06:00
CRDT- 2020/09/19 20:09
PHST- 2020/06/08 00:00 [received]
PHST- 2020/09/11 00:00 [revised]
PHST- 2020/09/14 00:00 [accepted]
PHST- 2020/09/20 06:00 [pubmed]
PHST- 2021/03/11 06:00 [medline]
PHST- 2020/09/19 20:09 [entrez]
AID - S0014-4886(20)30297-1 [pii]
AID - 10.1016/j.expneurol.2020.113466 [doi]
PST - ppublish
SO  - Exp Neurol. 2020 Dec;334:113466. doi: 10.1016/j.expneurol.2020.113466. Epub 2020 
      Sep 17.